Citations

Introduction There is uncertainty about the number of shark bites on humans in Florida (FL). Methods The International Shark Attack File (ISAF) and Global Shark Attack File (GSAF) databases (2016–2024) were compared with the non-inpatient FL Ambulatory and Emergency Department Patient Data database (AHCA) (2018–2023) and the National Emergency Medical Services (EMS) Information System (NEMSIS) (2016–2024). Results Between 2016–2024 there were 244 FL shark encounters reported in ISAF (mean 27.1 per year), 214 in GSAF (mean 23.8 per year), and 293 in a merged ISAF and GSAF (mean 32.6 per year). Between 2020–2023, there were 373 FL shark encounters reported in AHCA (mean 62.2 per year) compared with 114 encounters reported in NEMSIS (mean 22.8 per year) for 2020–2024. The rate ratio for AHCA FL shark encounters compared to the merged ISAF and GSAF was 1.91 (95% CI 1.64–2.23); p < .001. The percentage of shark encounters in Volusia County, FL, compared with all of FL shark encounters showed no significant differences between the ISAF and GSAF (40.2% and 33.6%, respectively) ( p = .16) and between the AHCA and NEMSIS (7.2% and 7.5%, respectively) ( p = 1.0). However, when comparing either ISAF or GSAF with either AHCA or NEMSIS, there were significant differences ( p < .001 for all). Discussion The AHCA dataset identified about twice as many shark bites as either the ISAF or GSAF. Many FL shark encounters did not require EMS or admission to the hospital. The discrepancy in the number of shark encounters attributed to Volusia County, FL, varied based on the dataset being examined.

Cardiovascular disease (CVD) remains the leading cause of death worldwide and is a major driver of critical illness, resulting in admission to cardiac intensive care units (CICUs). Patients with acute, life-threatening CVD often experience episodes of acute decompensation characterized by high symptom burden that may portend progressive loss of function, significantly impair quality of life (QOL), and involve high-intensity, technologically advanced therapies to sustain life. Despite these advances, up to 30% of patients die during CICU hospitalizations, and those who survive may subsequently face persistent functional impairment and psychosocial distress. During critical CVD (CCVD), patients often endure prognostic uncertainty and face complex decisions regarding life-sustaining therapies alongside refractory symptoms. Thus, care that focuses exclusively on disease-directed or life-prolonging therapies is often insufficient to address the full spectrum of patient and caregiver needs. When integrated alongside intensive cardiovascular care, palliative care (PC) offers a complementary and essential approach to the management of CCVD to inform therapeutic decisions, improve QOL, and address psychosocial and spiritual well-being. In this article, a multidisciplinary team featuring PC clinicians (physicians, nurse practitioners, social worker, psychologist, and chaplain), cardiologists, cardiac surgeons, cardiothoracic anesthesiologists, and intensivists present evidence-based guidance in a “Top Ten Tips” format to support PC clinicians caring for CICU patients and their caregivers.

ABSTRACT Background and Aims Autoimmune hepatitis is an immune‐mediated liver disease characterized by chronic inflammation and progressive fibrosis. Tissue‐resident memory T cells mediate organ‐specific immunity, but their role in autoimmune hepatitis remains poorly understood. We characterized tissue‐residency‐associated T‐cell populations and their cytokine profiles, assessed associations with disease severity and determined whether these signatures were reflected in peripheral blood. Methods Paired blood and liver samples were obtained from 19 patients with autoimmune hepatitis. Comparator cohorts included 20 patients with metabolic dysfunction‐associated steatotic liver disease and 20 surgical patients providing non‐inflamed adjacent non‐tumorous liver tissue. Multiparameter flow cytometry assessed tissue‐residency markers, T‐cell differentiation and cytokine production after polyclonal stimulation. Immune phenotypes were correlated with histological and clinical parameters. Results Autoimmune hepatitis was associated with compartment‐specific remodelling of T‐cell differentiation states and intrahepatic enrichment of CD8 + T cells expressing CD69, CD103 and CXCR6 relative to paired blood and comparator liver tissues. Intrahepatic CD8 + T cells exhibited an interferon‐γ‐dominant cytokine profile, whereas CD4 + T cells showed broader interferon‐γ‐, interleukin‐17A‐ and interleukin‐4‐associated responses. Despite the enrichment of tissue‐residency‐associated CD8 + T cells, cytokine‐producing CD8 + T‐cell populations with and without a tissue‐resident memory phenotype contributed comparably to the hepatic T‐cell compartment. Tissue‐residency‐associated phenotypes correlated positively with Ishak fibrosis stage, whereas the frequency of interferon‐γ‐positive intrahepatic CD8 + T cells correlated inversely with fibrosis. Conclusions Autoimmune hepatitis was characterized by intrahepatic accumulation of phenotypically distinct and functionally active CD8 + tissue‐resident memory T cells associated with fibrosis. This immune profile was not reflected in paired blood, indicating compartmentalized hepatic immune remodelling.

Abstract Context Menstrual irregularities have been associated with cardiovascular disease (CVD) risk, but underlying etiologies may confer distinct risk profiles. Functional hypothalamic amenorrhea (FHA) has not been evaluated as a separate risk phenotype. Objective To assess the association between FHA phenotype and incident CVD and cardiometabolic risk factors. Design Prospective cohort study with biennial follow-up from 1993 to 2019. Setting Nurses’ Health Study II cohort. Participants The sample included 52,655 premenopausal women free of CVD in 1993. FHA phenotype was defined as irregular or absent cycles without PCOS traits combined with low body mass index and/or high physical activity. Intervention None Main Outcome Measures Incident CVD (coronary heart disease [CHD; myocardial infarction or coronary revascularization] and stroke) and incident elevated cholesterol, hypertension, and type 2 diabetes (T2DM). Results During up to 26 years of follow-up, 1,007 CVD events occurred. Among women who developed CVD, the median time to the first CVD event was 17.0 years (IQR, 11.3-21.0). FHA phenotype in mid-adulthood was associated with a 62% higher risk of CVD (95% confidence interval [CI]: 1.01–2.59), driven by an almost two-fold higher risk of CHD (hazard ratio [HR] = 1.91; 95% CI: 1.11–3.27), compared with women with regular cycles. FHA was also associated with T2DM (HR = 1.86; 95% CI: 1.41–2.47), but not hypertension or elevated cholesterol. Non-FHA menstrual irregularity was associated with elevated cholesterol, hypertension, and T2DM, but not CVD. FHA in early adulthood was not associated with outcomes. Conclusions FHA phenotype in mid-adulthood was associated with increased CHD risk independent of traditional risk factors. Menstrual history may serve as an early marker of cardiometabolic risk.

Abstract Recent evidence implicates somatic mutations in disease-associated genes across multiple neurodegenerative disorders, including the identification of two somatic TARDBP variants as a putative cause of frontotemporal lobar degeneration with TDP-43 pathology type C (FTLD-TDP type C). However, these findings remain anecdotal. We performed single-nucleus amplicon sequencing of 39,800 neurons from the superior temporal gyrus of sporadic FTLD-TDP type C patients (34,738 neurons, 52 individuals) and non-demented controls (5,062 neurons, 26 individuals) using the Mission Bio Tapestri platform and investigated somatic variants in TARDBP and other FTLD-TDP-associated genes in a case-control setting. We uncovered an extensive landscape of ultra-low-frequency (<1%) somatic mutations across all analysed genes, including TARDBP . Rare somatic occurrences of known ALS/FTD-associated germline TARDBP variants, including p.N267S and p.M337V, were identified exclusively in patients. Among all targeted genes, TARDBP had the highest proportion of neurons harbouring a somatic variant, and this mutational burden was lower in individuals who died at an older age. Strikingly, the C-terminal domain of TDP-43, where most ALS/FTD germline pathogenic variants reside, exhibited a lower neuronal mutational burden than its other domains. This suggests that neurons harbouring damaging mutations may undergo progressive loss prior to autopsy, leaving only rare survivors at frequencies too low to detect by bulk or small-scale single-cell approaches. Together, our findings provide an unprecedented resolution into the somatic mutational landscape of post-mitotic neurons in FTLD-TDP type C and reveal a gene-specific layer of neuronal mosaicism that current single-cell WGS studies fail to detect.

BET bromodomain inhibitors are efficacious as anti-inflammatory compounds, but clinical translation is hampered by dose-limiting toxicities from non-selective inhibition. We herein report compounds 16 and 26, based on previously reported 4-methyl-1,2,3-triazole-based inhibitor, DW34. 16 has a BRD4 BD1 Ki of 10 nM, and up to 13–38-fold selectivity for BRD4 BD1 over other BD2 domains, and an improved hERG affinity of 4.24 µM over DW34. 26, A biscyclopropyl analog of 16 showed further enhancement of BD1 selectivity over BD2 (26–203-fold), but exhibited more potent hERG inhibition. Compound 16 had improved liver and plasma clearance over DW34, with good biodistribution to the liver, and had an intracellular target-engagement affinity Ki of 92 nM, with reduction of Ccl2, Cxcl1, AST, and ALT in in vitro and in vivo mouse models of liver inflammation. 16 represents a useful lead for treating inflammatory liver diseases, with improved specificity, drug-like properties, and reduced hERG affinity.

ABSTRACT Background Evaluating fairness in artificial intelligence (AI) is essential before clinical implementation to prevent unintended harm across diverse patient populations. This study assesses performance differences of an image-based surgical site infection (SSI) detection model across age, gender, geography, race, and skin color. Methods Model development/validation study using retrospective, multicenter data across surgical subspecialties from adults who submitted an image of their incision via the electronic health record within 30 days of their procedure between 2019-2024. Area under receiver operating curve (AUROC) was compared by age (<55 vs. ≥55 years old), gender (male vs. female), geography (Rochester, Minnesota vs. Jacksonville, Florida vs. Scottsdale, Arizona vs. regional Minnesota/Wisconsin areas), race (White/Caucasian vs. non-White/Caucasian), and skin color (Fitpatrick I-III vs. IV-VI and Monk A-E vs. F-J). Results Training data contained 13,702 images from 4,274 patients between 2019-2022 (50.1% ≥55 years old; 63.2% female; 91.6% White/Caucasian; 58.5% Rochester, 17.3% Florida, 10.5% Arizona; 96.3% light skin tone), of which 1,348 images (9.8%) had an SSI. No differences in SSI detection existed for age, gender, race, or skin color (AUROC 0.83-0.87, p>0.09), however geographical differences were significant: lowest AUROC 0.83 (95% CI 0.77-0.88) vs. highest AUROC 0.87 (95% CI 0.84-0.89, p=0.01). Temporal validation using 4,242 images from 1,353 patients between 2022-2023 showed intact fairness across subgroups (ΔAUROC ≤0.06) except geography (ΔAUROC ≤0.16). Conclusions The model behaved fairly across age, gender, race, and skin color, however geographical differences persisted. These findings have practical implications underscoring the importance of evaluating bias in clinical AI before deployment.